17 June 2011. What happens in the womb may hold clues to what causes schizophrenia, according to a symposium at the 2011 International Congress on Schizophrenia Research (ICOSR). Held on 4 April 2011 in Colorado Springs, Colorado, the session offered new data and insights into some aspects of the prenatal environment that have been fingered in schizophrenia—specifically, maternal anemia, vitamin D deficiency, birth weight, and maternal infection with herpes simplex virus. The speakers also looked beyond the environment to discuss how their findings might dovetail with other areas of schizophrenia research, such as neuroscience and genetics.
Despite all the thinking outside of the epidemiological box, a sense that environmental factors have received too little attention in schizophrenia research infused the room. Yet, epidemiology has yielded some of the biggest and most reliable effect sizes in schizophrenia research, said John McGrath, University of Queensland, Wacol, Australia. As the warm-up act for the talks to follow, he said that environmental factors might explain much of the unexplained apparent heritability of schizophrenia.
Ironing out schizophrenia
The first speaker, session chair Mary Cannon, Royal College of Surgeons in Ireland, Dublin, wants to bring the study of environmental influences in schizophrenia back into the limelight. She noted that studies have connected obstetric complications, such as malnutrition or infection in the mother, to an increased likelihood of schizophrenia in her offspring (see Clarke et al., 2006; Cannon et al., 2002; Brown, 2011). These complications may include maternal iron deficiency or anemia, a disease marked by too few red blood cells or too little iron-containing hemoglobin within those cells. To determine whether the offspring of mothers with anemia have a heightened risk for schizophrenia, Cannon and colleagues reanalyzed data from an earlier study of everyone born in Helsinki, Finland, from 1951 to 1960 (Cannon et al., 1999).
Using National Register data, the researchers identified subjects with schizophrenia and randomly chosen control subjects. They used birth records to link subjects to data on their mothers’ hemoglobin levels during pregnancy, which enabled them to classify the mothers as having had moderate, severe, or no anemia. Regression analyses found a dose-response relationship between the mothers’ anemia and schizophrenia in their progeny. Compared to subjects born of mothers who tested normal for hemoglobin, those whose mothers had moderate anemia had a 1.6-fold increase in risk; those born of severely anemic mothers had a threefold increase. Low ponderal index also seemed to up the risk, suggesting a benefit of baby fat.
Seeking more definitive answers, the researchers pooled their findings with those from six other studies that had results relevant to the issue of whether anemia increases the risk of schizophrenia. The subsequent meta-analysis produced remarkably consistent results that mirrored those from the Finnish study. As to what underlies the association, Cannon said that iron may play a role, but she noted that their study lacked any measure of iron levels. She explained that prenatal iron deficiency forever disrupts the building of the myelin sheath in rat studies.
Shining a light on vitamin D
The next speaker, John McGrath, presented an overview of findings that connect schizophrenia to vitamin D deficiency during early development, including those from his own recent work. As SRF previously reported (see SRF related news story), he and his colleagues found an inverted U-shaped relationship between vitamin D levels at birth and the risk of developing schizophrenia. To explain the nonlinear relationship, McGrath suggested that some people may be vitamin D resistant. In any case, he and his colleagues are trying to replicate the finding in a larger Danish case-control study that will look also at single-nucleotide polymorphisms (SNPs).
According to McGrath, the brain has vitamin D receptors and “can pack its own lunch” in that neurons make their own vitamin D. Not only does the nutrient play a role in neurodevelopment, but McGrath said a lot of good evidence indicates that it protects neurons from harm. In light of these and other findings, McGrath said that epidemiology researchers should attach themselves “like Velcro” to neuroscience. He would like to see epidemiological studies crosslinked with clinical and brain studies, including those that use animal models. To address the problem that risk factors often travel in packs in obstetric epidemiological studies, he said that randomized controlled trials of interventions, such as vitamin D supplements, in at-risk groups might help tease them apart.
McGrath raised the possibility that vitamin D levels might explain a host of epidemiological phenomena in schizophrenia, such as the increased risk in subjects born in winter or spring, in dark-skinned migrants to certain nations, and in city dwellers. According to McGrath, low vitamin D might also magnify the adverse effects of exposure to stress.
A heavy genetic burden
The third speaker, Jaana Suvisaari, National Institute for Health and Welfare, Helsinki, Finland, presented findings from a study of the suspected link between birth weight and the later development of schizophrenia. Research supports a robust association between schizophrenia and low birth weight, but also implicates high birth weight, Suvisaari said. She and her colleagues thought that family characteristics associated with abnormal growth might be confounding the results. They reasoned that genes that predispose people to schizophrenia might also predispose them to adverse effects from environmental exposures early in development.
To test the hypothesis that low—and maybe high—birth weight interact with genetic risk to foster schizophrenia, Suvisaari and colleagues turned to a study started in 1998 in Finland. That study enrolled families thought to carry a high genetic risk for schizophrenia, either because they included at least two siblings with the disease or because they came from a genetically isolated, schizophrenia-prone region. Piggybacking on that study, the new one analyzed data on 1,051 subjects from 315 high-risk families. Based on information from birth records, the researchers divided birth weight into four categories, including the usual cutoff of less than 2,500 grams for the featherweight group.
In regression analyses, high but not low birth weight predicted increased risk for schizophrenia—not exactly what the researchers predicted. In any case, the results did not back a link between birth weight and psychotic disorders other than schizophrenia. As to why the findings contradict the weight of evidence supporting a link between low birth weight and schizophrenia, Suvisaari suggested that her study’s efforts to control shared familial influences on birth weight might have made the difference.
Thinking that gestational diabetes might explain why the heaviest babies were most likely to develop schizophrenia, Suvisaari and colleagues decided to investigate; however, they had to settle for a proxy measure of gestational diabetes—namely, diabetes in the mother. They found that maternal diabetes upped the risk for schizophrenia, but did so independently of birth weight. It could not explain the extra risk in the biggest babies.
When G and E look alike
The last speaker of the session, Preben Mortensen, Aarhus University, Aarhus, Denmark, talked about the challenge of untangling genetic and environmental factors, which may interact or correlate with each other or reflect unknown risk factors. While researchers have used family history to index genetic liability for schizophrenia, Mortensen said that psychiatric family history may also reflect environmental exposures and gene-environment interactions. In a new study, he and his colleagues found that variation in SNPs across the genome failed to explain the added risk of schizophrenia that comes with having a mentally ill parent. This supports Mortensen’s view that family history controls poorly for genetic liability.
A recent study by Mortensen and colleagues underscores the need to tease apart confounding and interacting variables (Mortensen et al., 2010). It used data from the Danish National Registers and the Newborn Biobank, which enabled them to check for antibodies that would reveal maternal infection with herpes simplex virus type 2 (HSV2). Analyses showed that the offspring of mothers with high levels of these antibodies were at heightened risk for developing schizophrenia (relative risk = 1.56). Adjusting for family history, particularly fathers’ mental illness, lessened the risk slightly. This hints that paternal psychiatric history played a confounding role, but whether that reflected the effects of genes or environment remains unclear.
Currently, Mortensen and colleagues are exploring the role of genetic variables in the excess schizophrenia risk that seems to come with having a mother infected with HSV2. Using a two-stage design, they first tested SNPs genomewide for associations with exposure to infection in healthy controls, and then followed up with case-control comparisons. Although they tied some SNPs to HSV2 antibody levels in controls, the SNPs did not account for the virus-schizophrenia connection. Now, the researchers are investigating whether interactions between genetic variants and inflammation might play a role.
Looking ahead, Mortensen said that each future study should include as wide a range of genetic and environmental variables as possible. He warned that confounding from gene-environment associations poses as much risk to genetic association studies as to their epidemiological cousins. According to Mortensen, “If we do not face the challenge of integrating epidemiology with genetics, we will likely miss central elements of schizophrenia etiology.”—Victoria L. Wilcox.